10-(2-Substituted-amino-ethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cycloheptenes

ABSTRACT

10-(2-substituted-aminoethyl)-10,11-dihydro-5-methylene-2 or 3 7 or 8-substituted or unsubstituted-5H-dibenzo[a,d]cycloheptenes e.g., 10-(2-dimethylaminoethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cycloheptene, prepared by various methods including acid dehydration of the corresponding dibenzo[a,d]cycloheptene-5-ols. The compounds are useful as anti-depressants.

This is a division of application Ser. No. 442,078 filed Feb. 13, 1974,now U.S. Pat. No. 3,994,961.

This application is a continuation-in-part of copending application Ser.No. 383,919, filed July 30, 1973 now abandoned, which in turn is acontinuation-in-part of copending application Ser. No. 368,652, filedJune 11, 1973, now abandoned, which in turn is a continuation-in-part ofcopending application Ser. No. 342,844, filed Mar. 19, 1973, nowabandoned, which in turn is a continuation-in-part of copendingapplication Ser. No. 325,909, filed Jan. 22, 1973, now abandoned, whichin turn is a continuation-in-part of copending application Ser. No.308,302, filed Nov. 20, 1972, now abandoned, which in turn is acontinuation-in-part of copending application Ser. No. 224,323, filedFeb. 7, 1972, now U.S. Pat. No. 3,925,476.

This invention relates to 5-methylene-5H-dibenzo[a,d]cycloheptenes. Moreparticularly, it relates to 10-(2-substitutedaminoethyl)-10,11-dihydro-5-methylene-2 or 3, 7 or 8-substituted orunsubstituted-5H-dibenzo[a,d]cycloheptenes, acid addition salts thereof,intermediates thereof, and processes for their preparation.

The compounds of this invention may be represented by the followingstructural formula: ##STR1## wherein

R₁ and R₂ each independently represent hydrogen or fluoro, and

R₃ ' and R₄ ' are each independently lower alkyl having 1 to 2 carbonatoms, i.e., methyl or ethyl, or one of R₃ ' and R₄ ' is hydrogen andthe other is methyl.

The compounds of formula (I) having the following structural formula arepreferred ##STR2## R₁ and R₂ are as defined above.

A preferred aspect of the invention is the compound10-(2-dimethylaminoethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cyclohepteneand10-(2-dimethylaminoethyl)-10,11-dihydro-7-fluoro-5-methylene-5H-dibenzo[a,d]cyclohepteneand pharmaceutically acceptable acid addition salts thereof.

The compounds of formula (I) in which R₃ ' and R₄ ' are lower alkyl aspreviously defined may be prepared by the following reaction scheme A:##STR3## wherein

R₁ and R₂ have the above stated significance and

R₃ and R₄ represent said lower alkyl.

The compounds of formula (Ia) may be prepared by treating a novelcompound of formula (II) with a dehydrating agent such as dilute orconcentrated mineral acids e.g. sulfuric acid, hydrochloric acid and thelike, iodine, phosphorus oxychloride, or thionyl chloride, an alkyl orarylsulfonyl chloride such as methanesulfonyl chloride orbenzenesulfonyl chloride or an inorganic acid or Lewis acid used in thesolid form. Examples of the last two acid types are potassiumbisulphate, boric acid, aluminum oxide, and silicon dioxide. Whenphosphorus oxychloride or thionyl chloride or an alkyl or arylsulfonylchloride is used as the dehydrating agent, it is preferred that an acidbinding agent such as a lower alkyl tertiary amine wherein alkyl isdefined as having 1 to 4 carbon atoms, e.g. triethylamine, be used. Thereaction utilizing these dehydrating agents as well as that using thesolid inorganic acids and Lewis acids may be conveniently carried out ininert hydrocarbons such as benzene, toluene and the like, at atemperature from about 50° C. to the reflux temperature of the reactionmedium, preferably the reflux temperature, for about 1 to 24 hours,preferably 1 to 4 hours. The preferred dehydration medium is 1M to 5Msulfuric acid. Neither the solvents nor the temperatures used arecritical.

The compounds of formula (II) may be prepared by the following reactionscheme B: ##STR4## wherein

R₁, R₂, R₃ and R₄ have the above stated significance, and

M is Li or MgY,

wherein Y is halo having an atomic weight of 35 to 127.

The compounds of formula (II) may be prepared by treating a compound offormula (III) with an organometallic reagent of formula (IV), e.g.methyllithium, and the like, in the presence of an inert atmosphere,e.g. nitrogen gas, in an inert solvent, such as diethyl ether,tetrahydrofuran, benzene, toluene and the like. When M is Li, at atemperature of from -20° to +25° C., preferably -5° to +5° C. for about5 to 45 minutes, preferably 10 to 20 minutes. When M is MgY at atemperature of 10° to 20° C, for about 1 to 6 hours, preferably 3 to 5hours, followed by standard hydrolysis of the resulting adduct, e.g.,water or aqueous ammonium chloride solution. Neither the solvents notthe temperatures used are critical.

The compounds of formula (III) are a further aspect of this inventionand may be prepared by the following reaction scheme C: ##STR5## whereinR₁, R₂, R₃ and R₄ have the above stated significance.

The compounds of formula (III) may be prepared by cyclization of acompound of formula (V) in a strong Lewis acid medium such as stannictetrachloride, ferric chloride, titanium tetrachloride and the like, orin strong mineral acid medium such as concentrated sulfuric acid,phosphoric acid, polyphosphoric acid and the like. When a Lewis acid isused, the reaction may be carried out in an inert solvent such asdichloromethane, carbon tetrachloride, carbon disulfide, nitrobenzeneand the like. A solvent is not necessary when a strong mineral acid isused but solvents such as those employed for the Lewis acid may beutilized. The cyclization may be carried out at a temperature from about20° to 150° C., preferably from about 100° to about 120° C., for about 2to 10 hours preferably for about 3 to 6 hours. The reaction may also berun at 140° C. overnight which is preferred in the preparation of thecompound where R₂ is fluorine, e.g.10-(2-dimethylaminoethyl)-10,11-dihydro-7-fluoro-5H-dibenzo[a,d]cyclohepten-5-one and acid addition salts thereof. Neither thesolvents nor the temperatures used are critical.

When using a Lewis acid, compound (V) may optionally be used in the formof the corresponding acid chloride. The acid chloride of compound (V)may be prepared by conventional techniques, e.g. treating compound (V)with thionyl chloride in a solvent such as methylene chloride. Thestraight chain 1-4 carbon alkyl esters of the acid (V), preparedtherefrom by conventional techniques, may optionally be utilized inplace of the corresponding acid, and otherwise under the same conditionsdescribed above to obtain compounds (III).

As a further aspect of their invention, the compounds of formula (Ia)may also be prepared by the following reaction scheme D: ##STR6## whereR₁, R₂, R₃ and R₄ have the above stated significance.

The compounds of formula (Ia) may be prepared by treating a compound offormula (VI) with sodium hydride in the presence of an inert organicsolvent such as diethyl ether, hexane, heptane or tetrahydrofuran, thelatter being especially preferred. The temperature of the reaction isnot critical but it is preferred that the reaction be carried out attemperatures between about -10° to +10° C., especially -5° to +5° C. Thereaction may be run for 2 to 10 hours, preferably 4 to 6 hours. Theparticular solvent used and the reaction time are not critical.

The compounds of formula (VI) are prepared by the following reactionscheme E: ##STR7## where R₁, R₂, R₃ and R₄ have the above statedsignificance.

The compounds of formula (VI) are prepared by treating a compound of theformula (III) with a Grignard reagent of the formula (VII) in thepresence of an inert organic solvent such as tetrahydrofuran, heptane,hexane, or diethylether, the latter being especially preferred. Thetemperature of the reaction is not critical, but it is preferred thatthe reaction be carried out at the reflux temperature of the solvent.The reaction may be run for 2 to 10 hours, preferably 4 to 6 hours,followed by standard hydrolysis of the resulting adduct, preferably withaqueous ammonium chloride. Neither the solvents nor the reaction timesused are critical.

The compounds of formula (Ia) may also be prepared by another inventiveprocess as represented by the following reaction scheme F: ##STR8##where R₁, R₂, R₃ and R₄ have the above stated significance.

The compounds of formula (Ia) are prepared by treating a compound of theformula (VIII) with lithium in the presence of liquid ammonia and in thepresence of an inert atmosphere, e.g. nitrogen, helium, or argon at thereflux temperature of the system. Although a solvent is unnecessary, itis preferred that the reaction be carried out in the presence of aninert organic solvent such as tetrahydrofuran or diethylether, thelatter being especially preferred. The temperature of the reaction isnot critical, but it is preferred that the reaction be carried out atthe reflux temperature of the system. Although the reaction time is notcritical, it is preferred that the reaction be run from about 15 to 45minutes, especially 25 to 35 minutes.

The compounds of formula (VIII) are prepared according to the followingreaction scheme G: ##STR9## where

Z is alkyl having 1 to 4 carbon atoms, and

R₁, R₂, R₃ and R₄ have the above stated significance.

The compounds of formula (VIII) are prepared by treating a compound offormula (IX) with an alkyl lithium such as butyllithium in liquidammonia under nitrogen atmosphere at reflux temperature of the systemfollowed by benzoyl chloride in the presence of an inert organicsolvent, such as tetrahydrofuran, heptane, hexane or diethylether, thelatter being especially preferred. The temperature of the reaction isnot critical, but it is preferred that the reaction be carried out attemperatures between about 10° to 40° C., especially from about 20° to30°. Although the reaction time is not critical, it is preferred thatthe reaction be run from about 1 to 5 hours, preferably from about 2 to3 hours.

The compounds of formula (IX) are prepared according to the followingreaction scheme H: ##STR10## where R₁, R₂, R₃ and R₄ have the abovestated significance.

The compounds of formula (IX) are prepared by treating a compound of theformula (III) with phenylthiomethyllithium under an inert atmospheresuch as nitrogen, helium, or argon in the presence of an inert organicsolvent such as diethylether, heptane, hexane or tetrahydrofuran, thelatter being especially preferred. The temperature of the reaction isnot critical, but it is preferred that the reaction be carried out attemperatures between about 10° to 40° C. especially from about 20° to30° C. The reaction may be run from about 15 to 30 hours; preferablyfrom about 20 to 25 hours.

According to a still further aspect of this invention, the compounds offormula (Ia) may be prepared according to the following reaction schemeJ: ##STR11## where R₁, R₂, R₃ and R₄ have the above stated significance.

The compounds of formula (Ia) may be prepared by treating a compound ofthe formula (X) with triphenylphosphine optionally in an inert organicsolvent such as tetrahydrofuran, benzene, toluene or the like,tetrahydrofuran being especially preferred. The temperature of thereaction is not critical but it is preferred that the reaction becarried out at temperatures from about 160° to 200° C., preferably 175°to 185° C. The reaction may be run from about 3 to 8 hours, preferably 4to 6 hours.

The compounds of formula (X) are prepared according to the followingreaction scheme K: ##STR12## where

X is halo having an atomic weight from about 35 to 80, and

R₁, R₂, R₃ and R₄ have the above stated significance.

The compounds of formula (X) are prepared by treating a compound offormula (III) with trimethyloxosulfonium halide such astrimethyloxosulfonium iodide followed by sodium hydride in the presenceof dimethyl sulfoxide. The temperature of the reaction is not criticaland it is preferred that the reaction be carried out at temperaturesfrom about 10° to 60° C., preferably 20° to 50° C. Although the reactiontime is not critical, it is preferred that the reaction be run fromabout 10 minutes to 2 hours, preferably 15 minutes to 1.5 hours.

The compounds of formula (Ia) as an additional aspect to this inventionare prepared according to the following reaction scheme L: ##STR13##where R₁, R₂, R₃ and R₄ have the above stated significance.

The compounds of formula (Ia) are prepared by treating a compound of theformula (III) with methyltriphenylphosphonium bromide followed by sodiumhydride in the presence of dimethyl sulfoxide. Although the temperatureof the reaction is not critical, it is preferred that the reaction becarried out at temperatures from about 10° to 40° C., preferably 20° to30° C. The reaction may be run from about 30 minutes to 1.5 hours.

The compounds of formula (III) may also be prepared according to thefollowing reaction scheme M: ##STR14## where R₁, R₂, R₃, R₄ and Z havethe above stated significance.

The compounds of formula (III) may be prepared by cyclization of acompound of the formula (XI) in a strong mineral acid such asconcentrated sulfuric acid, phosphoric acid or polyphosphoric acid, thelatter being preferred. The reaction may be carried out in an inertsolvent such as dichloromethane, carbon disulfide, or carbontetrachloride, preferably carbon tetrachloride. The cyclization may becarried out at a temperature from about 20° to 150° C., preferably fromabout 110° to 130° C. The reaction may be run from about 2 to 10 hours,preferably from about 5 to 7 hours. Neither the solvents, times nor thetemperatures used are critical.

The compounds of formula (XI) are prepared according to the followingreaction scheme N: ##STR15## where R₁, R₂, R₃, R₄ and Z have the abovestated significance.

The compounds of formula (XI) are prepared by reacting a compound of theformula (V) with a non-aqueous mineral acid such as gaseous hydrogenchloride or concentrated sulfuric acid in the presence of an inertorganic solvent such as the 1-4 carbon alkanols, e.g. methanol, ethanoland the like. Although the temperature of the reaction is not critical,it is preferred that the reaction be run from about 20° to 60° C.,preferably the reflux temperature of the solvent. The reaction may berun from about 12 to 24 hours, preferably 17 to 19 hours.

The compounds of formula (V) may be prepared by the following reactionscheme P: ##STR16## where R₁, R₂, R₃ and R₄ have the above statedsignificance.

The compounds of formula (V) may be prepared by hydrogenating a compoundof formula (XII) in the presence of a noble metal catalyst such aspalladium, platinum, rhodium and the like, optionally neat or on asupport such as charcoal, at an atmosphere of from 35 to 100 psipreferably 50 to 55 psi, in an inert lower alkanol having 1 to 4 carbonatoms, such as methanol, ethanol, propanol,, isopropanol, butanol,isobutanol, or an acetic acid, at a temperature of from 20° to 80° C.preferably 25° to 35° C., until one equivalent amount of hydrogen isabsorbed. To enhance the reaction, aqueous mineral acid such ashydrochloric acid, sulfuric acid, or perchloric acid may be added to thereaction medium. Neither the solvents, temperatures or pressures usedare critical.

A further method of preparing compounds (V) by compounds (XII) is shownby the following reaction scheme Q: ##STR17## where R₁, R₂, R₃ and R₄have the above stated significance.

The compounds of formula (V) may be prepared according to reactionscheme Q by reducing a compound of formula (XII) using a zinc-ammoniumhydroxide reduction system optionally in the presence of cupric sulfate.Although the particular solvent used is not critical, it is preferredthat the reaction be carried out in the presence of an inert organicsolvent such as the lower alkanols, e.g. methanol, ethanol and the like,especially ethanol. The temperature of the reaction is not critical, butit is preferred that the reaction be carried out at temperatures fromabout 60° to 100° C., preferably 75° to 85° C. The reaction may be runfrom about 24 to 48 hours, preferably 28 to 30 hours.

The compounds of formula (XII) may be prepared by the following reactionscheme R: ##STR18## where

R₁, R₂, R₃ and R₄ have the above stated significance, and

R₆ represents lower alkyl, as previously defined.

The compounds of formula (XII) are prepared by heating a compound offormula (XIII) optionally in an inert solvent such as tetrahydrofuran,the hydrocarbons or halogenated hydrocarbons such as hexane, heptane,benzene, toluene, o-dichlorobenzene and the like, at about 60° to 220°C., preferably about 140° to 160° C. for about 15 to 48 hours,preferably about 20 to 28 hours. The temperatures and times used are notcritical. To improve yields and obtain a better quality product, thereaction may be performed under inert atmosphere, e.g. nitrogen gas.

The compounds of formulas (I), (II), (III), (V), (VI), (VIII), (IX), and(X) may exist in the form of their acid addition salts. Said salts andtheir respective free bases may be converted from one to the other byconventional techniques and are chemically interchangeable for purposesof the above described processes.

The compounds of formula (XIII) may be prepared as indicated by thefollowing reaction scheme S: ##STR19## where R₁, R₂, R₃, R₄ and R₆ havethe above stated significance.

The compounds of formula (XIII) are prepared by condensing a compound offormula (XIV) with a compound of formula (XV) in the presence of inertatmosphere, e.g. nitrogen gas, in an inert solvent such as diethylether, tetrahydrofuran, hexane, heptane, benzene and the like ormixtures thereof, and subjecting the reaction mixture to hydrolysis,preferably with aqueous ammonium chloride. The condensation may becarried out at a temperature of from -30° to -15° C., preferably -25° to-20° C. for about 1 to 3 hours. The hydrolysis is performed inconventional manner at a temperature of about -15° to -5° C. Neithertemperatures, solvents, nor hydrolyzing agents used are critical.Compound (XV) is preferably added in inert solvent to a cold (-30° C. to-15° C.) inert solvent solution of compound (XIV).

Another aspect of this invention is the preparation of the compounds offormula (I) in which one of R₃ ' and R₄ ' is hydrogen and the other ismethyl. These compounds may be prepared according to the followingreaction scheme: ##STR20## where R₁ and R₂ are as defined above.

The compounds of formula (Ib) are prepared by treating a compound of theformula (XVI) with an alkali metal hydroxide, such as potassiumhydroxide, sodium hydroxide and lithium hydroxide, preferably potassiumhydroxide in the presence of an inert organic solvent. Although theparticular solvent used is not critical, it is preferred that thereaction be carried out in the presence of dimethylacetamide,dimethylformamide or the lower alkanols, e.g., methanol, ethanol and thelike, preferably ethanol. The temperature of the reaction is notcritical, but it is preferred that the reaction be run from about 80° to150° C, preferably the reflux temperature of the solvent. The reactionis run from about 5 to 24 hours, preferably from about 8 to 12 hours.

The compounds of formula (XVI) may be prepared according to thefollowing reaction scheme: ##STR21## where

Et represents ethyl and

R₁ and R₂ are as defined above.

The compounds of formula (XVI) are prepared by treating a compound ofthe formula (Ia) with a compound of the formula (XVII) in the presenceof an inert organic solvent. Although the particular solvent employed innot critical, it is preferred that the reaction be carried out in thepresence of the aromatic hydrocarbons such as benzene, toluene, xyleneand the like, preferably toluene. The temperature of the reaction is notcritical, but it is preferred that the reaction be run from about 80to-180° C, preferably the reflux temperature of the solvent. Thereaction is run from about 12 to 48 hours, preferably from about 16 to20 hours.

The compounds of formulas (I), (II), (III), (V), (VI), (VII), (IX), (X),(XI), (XII) and (XVI) may be recovered using conventional techniquessuch as crystallization, evaporation, or filtration.

Certain of the compounds of formulas (IV), (VII), (XIV), (XV) and (XVII)are known and may be prepared by methods disclosed in the literature.Those compounds (IV), (VII), (XIV), (XVII) not specifically disclosedmay be prepared by analogous methods from known materials.

It will be understood that certain of the compounds of formulas (I),(II) and (III) exist in racemic form or in the form of optically activeisomers. The separation and recovery of the respective isomers may bereadily accomplished employing conventional techniques and such isomersare included within the scope of this invention.

The compounds of formula (I) are useful because they possesspharmacological activity in animals. More particularly, the compounds offormula (I) are useful as anti-depressants agents as indicated by theiractivity in mice given intraperitoneally 0.1 to 25 mg/kg of body weightof active material, and tested by the method basically as described bySpencer, P.S.J., Antagonism of Hypothermia in the Mouse byAntidepressant Drugs, pp. 194-204, Ed. S. Garattini and M.N.G. Dukes,Excerpta Medica Foundation, 1967, and by their activity in the cat giventypically 0.25-2.0 mg/kg of body weight of active material and testedfor their effect on 5-hydroxytryptophan and 1-tryptophan induced spinalmonosynaptic reflex transmission, basically as described by Anderson E.G. and Shibuya T., the Effects of 5-Hydroxytryptophan and 1-tryptophanon Spinal Synaptic Activity, pp. 352 to 360, J. of Pharm. and Exp.Therapeutics, Vol. 153, No. 2, 1966.

When so utilized, the compounds may be combined with one or morepharmaceutically acceptable carrier or adjuvants. They may beadministered orally or parenterally and, depending upon the compoundemployed and the mode of administration, the exact dosage utilized mayvary.

Furthermore, the compounds (I) may be similarly administered in the formof their non-toxic pharmaceutically acceptable acid addition salts. Suchsalts possess the same order of activity as the free base, are readilyprepared by reacting the base with an appropriate acid and accordingly,are included within the scope of the invention. Representative of suchsalts are the mineral acid salts, such as the hydrochloride,hydrobromide, sulfate, phosphate and the like and the organic acidsalts, such as succinate, benzoate, acetate, p-toluenesulfonate,benzenesulfonate, maleate and the like.

As noted above, the compounds of formula (I) exist as optical isomers.In some cases, greater pharmacological activity or other beneficialattributes may be found for a particular isomer and in such instances,administration of such isomers may be preferred.

In general, satisfactory results are obtained when the compounds areadministered as anti-depressants at a daily dosage of from about 0.5 to100 milligrams per kilogram of animal body weight. This daily dosage ispreferably given in divided doses, e.g., 2 to 4 times a day, or insustained release form. For most large animals, the total daily dosageis from about 30 to 750 milligrams and dosage forms suitable forinternal administration comprise from about 7.5 to 375 milligrams of thecompound in admixture with a solid or liquid pharmaceutical carrier ordiluent.

EXAMPLE 12-(β-[2-dimethylaminoethyl]-β-hydroxyphenethyl)-N-methylbenzamide

To a flask equipped with a stirrer, dropping funnel, condenser and gasinlet tube maintained under a nitrogen atmosphere there is added at roomtemperature 40.0 g. (0.28 mole) of o-methyl-N-methyl benzamide and 250ml. of anhydrous tetrahydrofuran. The reaction flask is immersed in anice bath and cooled to an internal temperature of 5° C. Stirring isinitiated and 360 ml. of 1.6 M. n-butyllithium (0.616 mole) in hexane isadded dropwise for about 1 hour maintaining the temperature below 8° C.The resulting red dilithio salt (compound VIII) is stirred at 5° C. for1 additional hour and the reaction flask is then immersed in a dry-iceacetone bath and cooled to an internal temperature of -30° C. To thecold reaction mixture a solution of 49.7 g. (0.28 mole)3-dimethylaminopropiophenone in 140 ml. anhydrous tetrahydrofuran isadded dropwise in ca. 45 minutes maintaining the temperature between-30° and -20° C. The resulting reaction mixture is stirred at -25° C.for 1 hour, allowed to warm to -10° C. in ca. 1 hour, and then treatedwith 200 ml. of saturated aqueous ammonium chloride while maintainingthe temperature below 0° C. The resulting solid in filtered, washedthoroughly with water and recrystallized from methylene chloride-ether(1:1) to give2-(β-[2-dimethylaminoethyl]-β-hydroxyphenethyl)-N-methylbenzamide; m.p.139.5° to 140.5° C.

When the above process is carried out and in place of o-methyl-N-methylbenzamide there is used

(a) 4-fluoro-N,2-dimethylbenzamide,

(b) N,2-dimethylbenzamide

(c) N,2-dimethylbenzamide,

(d) o-methyl-N-ethylbenzamide, or

(e) 4-fluoro-N,2-dimethylbenzamide,

and in place of 3-dimethylaminopropiophenone there is used,

(a) 4'-fluoro-3-dimethylaminopropiophenone,

(b) 4'-fluoro-3-dimethylpropiophenone,

(c) 3'-fluoro-3-dimethylpropiophenone,

(d) 3-diethylaminopropiophenone, or

(e) 3-dimethylaminopropiophenone,

and reacting the correspondingly lettered benzamides and propiophenones,there is obtained,

(a)4-fluoro-2-(4-fluoro-β-[2-dimethylaminoethyl]-β-hydroxyphenethyl)-N-methylbenzamide,or

(b)2-(4-fluoro-β-[2-dimethylaminoethyl]-β-hydroxyphenethyl)-N-methylbenzamide

(c)2-(3-fluoro-β-[2-dimethylaminoethyl]-β-hydroxyphenethyl)-N-methylbenzamide,(d) 2-(β-[2-diethylaminoethyl]-β-hydroxyphenethyl-N-methylbenzamide, or

(e)4-fluoro-2-(β-[2-dimethylaminoethyl]-β-hydroxyphenethyl)-N-methylbenzamide,respectively.

EXAMPLE 2 3-[2-dimethylaminoethyl]-3,4-dihydro-3-phenylisocoumarin

To a flask equipped with a stirrer, condenser and gas inlet tubemaintained under a nitrogen atmosphere there is added at roomtemperature 16.3 g (0.05 mole) of2-(β-[2-dimethylaminoethyl]-β-hydroxyphenethyl)-N-methylbenzamide and170 ml of o-dichloro benzene. Stirring is initiated and the mixture isheated at reflux for 18 hours. The excess o-dichlorobenzene is thenremoved by distillation in vacuo and the resulting oil is crystallizedfrom ether to give3-[2-dimethylaminoethyl]-3,4-dihydro-3-phenylisocoumarin; m.p.95.0°-95.5° C.

When the above process is carried out and in place of2-(β-[2-dimethylaminoethyl]-β-hydroxyphenethyl)-N-methylbenzamide, thereis used

(a)4-fluoro-2-(4-fluoro-β-[2-dimethylaminoethyl]-β-hydroxyphenethyl)-N-methylbenzamide,

(b)2-(4-fluoro-β-[2-dimethylaminoethyl]-β-hydroxyphenethyl)-N-methylbenzamide,

(c)2-(3-fluoro-β-[2-dimethylaminoethyl]-β-hydroxyphenethyl)-N-methylbenzamide,

(d) 2-(β-[2-diethylaminoethyl]-β-hydroxyphenethyl)-N-methylbenzamide, or

(e)4-fluoro-2-(β-[2-dimethylaminoethyl]-β-hydroxyphenethyl)-N-methylbenzamide,

there is obtained

(a) 6-fluoro-3-(4-fluorophenyl)-3-(2-dimethylaminoethyl)-3,4dihydroisocoumarin;

(b) 3-(4-fluorophenyl)-3-(2-dimethylaminoethyl)-3,4-dihydroisocoumarin,

(c) 3-(3-fluorophenyl)-3-(2-dimethylaminoethyl)-3,4-dihydroisocoumarin,

(d) 3-(2-diethylaminoethyl)-3,4-dihydro-3-phenylisocoumarin, or

(e) 6-fluoro-2-(2-dimethylaminoethyl)-3,4-dihydro-3-phenylisocoumarin,respectively.

EXAMPLE 310-(2-dimethylaminoethyl)-10,11-dihydro-5-methylene,5H-dibenzo[a,d]cycloheptene maleate Step a 2-(β-[2-dimethylaminoethyl]phenethyl)benzoicacid hydrochloride

A solution of 14.75 g. (0.05 mole) of3-(2-dimethylaminoethyl)-3,4-dihydro-3-phenylisocoumarin in 150 ml.ethanol containing 1 g. 10% palladium on charcoal is hydrogenated at 50psi and room temperature until one equivalent of hydrogen is absorbed.The mixture is filtered and evaporated to give the intermediate2-(β-[2-dimethylaminoethyl]phenethyl) benzoic acid hydrochloride, m.p.152° to 154° C.

Step b 10-(2-dimethylaminoethyl)-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5-one hydrochloride

A mixture of 14.75 g (0.05 mole) of 2-(β-[2-dimethylaminoethyl]phenethyl)benzoic acid hydrochloride and 150 g polyphosphoric acid isheated at 110° C for 6 hrs. allowed to cool and poured onto crushed icewith stirring. The resulting solution is cooled on ice and made basic bythe addition of solid potassium hydroxide, and extracted with methylenechloride. The methylene chloride is washed with water, dried overanhydride magnesium sulfate and evaporated in vacuo. The residue isdissolved in isopropanol, and treated with gaseous hydrogen chloride.The resulting precipitate is filtered and recrystallized fromisopropanol to give the intermediate10-(2-dimethylaminoethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-onehydrochloride, m.p. 188°-190° C.

Following the above procedure and using an equivalent amount of ferricchloride in place of polyphosphoric acid, there is obtained theidentical product.

Similarly using ferric chloride and2-(β-[2-dimethylaminoethyl]-phenethyl)benzoic acid chloride in place of2-(β-[2-dimethylaminoethyl] phenethyl)benzoic acid hydrochloride, theidentical product is again obtained.

Following the above detailed procedure out using 16.3 g. of2-(p-[2-dimethylaminoethyl]phenethyl)benzoic acid ethyl ester in placeof 14.75 g. of 2-(β-[2-dimethylaminoethyl]phenethyl)benzoic acidhydrochloride, there is obtained10-(2-dimethylaminoethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-onehydrochloride, m.p. 188° to 190° C.

Step c10-(2-dimethylaminoethyl)-10,11-dihydro-5-methyl-5H-dibenzo[a,d]cyclohepten-5-ol

To a solution of 19.4 g. (0.07 mole) of10-(2-dimethylaminoethyl)-10,11-dihydro-5H-dibenzo[ad,]cyclohepten-5-onein 200 ml. diethylether, under nitrogen, cooled to -5° C. 70 ml. 1.5Nmethyllithium (0.105 mole) in diethylether is added dropwise withstirring, maintaining temperature below 0° C., 15 minutes after theaddition is complete the reaction is quenched by the addition of 50 ml.saturated ammonium chloride solution. The organic layer is separated,extracted with saturated sodium chloride solution, dried over anhydrousmagnesium sulfate and evaporated. The crystalline residue isrecrystallized from methylenechloride-methanol 1:1 to give theintermediate10-(2-dimethylaminoethyl)-10,11-dihydro-5-methyl-5H-dibenzo[a,d]cyclohepten-5-ol,m.p. 161.5° to 162° C.

Following the above procedure and using an equivalent amount ofmethylmagnesiumchloride in place of methyllithium at room temperatureinstead of 0° C. for 3 hours instead of 15 minutes, the identicalproduct is again obtained.

Step d10-(2-dimethylaminoethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate

A mixture of 8g (0.027 mole) of10-(2-dimethylaminoethyl)-10,11-dihydro-5-methyl-5H-dibenzo[a,d]-cyclohepten-5-oland 250 ml 2M-sulfuric acid is refluxed for 2 hrs. The mixture is cooledin ice and made basic by the addition of solid potassium hydroxide. Themixture is extracted with methylene chloride. The methylene chloride iswashed with water, dried over anhyd. magnesium sulfate and evaporated invacuo. The oily residue is distilled at 140° C/0.5 mm and the distillateis dissolved in ethanol and treated with maleic acid. The precipitate isfiltered and recrystallized from diethylether-ethanol 1:1 to give theproduct10-(2-dimethylaminoethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate, m.p. 171°-172° C.

(1) Following the above procedure and using an equivalent amount offerric chloride in place of sulfuric acid, there is obtained theidentical product.

EXAMPLE 4 Step a

Following the procedure of Example 3, step a)and in place of3-(2-dimethylaminoethyl)-3,4-dihydro-3-phenylisocoumarin, and startingwith;

(a) 3-(4-fluorophenyl)-3-(2-dimethylaminoethyl)-3,4-dihydro-6-fluoroisocoumarin,

(b) 3-(4-fluorophenyl)-3-(2-dimethylaminoethyl)-3,4-dihydroisocoumarin,

(c) 3-(3-fluorophenyl)-3-(2-dimethylaminoethyl)-3,4-dihydroisocoumarin,

(d) 3-(2-diethylaminoethyl)-3,4-dihydro-3-phenylisocoumarin, or

(e) 6-fluoro-3-(2-dimethylaminomethyl)-3,4-dihydro-3-phenylisocoumarin,

the following intermediates are obtained,

(a) 4-fluoro-2-(β-[2-dimethylaminoethyl]-p-fluorophenethyl)benzoic acidhydrochloride,

(b) 2-(β-[2-dimethylaminoethyl]-p-fluorophenethyl)benzoic acidhydrochloride,

(c) 2-(β-[2-dimethylaminoethyl]-m-fluorophenethyl)benzoic acidhydrochloride,

(d) 2-(β-[2-diethylaminoethyl])benzoic acid hydrochloride, or

(e) 4-fluoro-2-(β-[2-dimethylaminoethyl])benzoic acid hydrochloride,respectively.

Step b

Following the procedure of Example 3, step (b) and in place of2-(β-[2-dimethylaminoethyl]phenethyl)benzoic acid hydrochloride, andstarting with the correspondingly lettered intermediate of step a) ofthis example, the following intermediates are obtained.

(a)10-(2-dimethylaminoethyl)-10,11-dihydro-2,7-difluoro-5H-dibenzo[a,d]cyclohepten-5-onehydrochloride,

(b)10-(2-dimethylaminoethyl)-10,11-dihydro-7-fluoro-5H-dibenzo[a,d]cyclohepten-5-onehydrochloride.

(c)10-(2-dimethylaminoethyl)-10,11-dihydro-8-fluoro-5H-dibenzo[a,d]cyclohepten-5-onehydrochloride,

(d)10-(2-diethylaminoethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-onehydrochloride, or

(e)10-(2-dimethylaminoethyl)-10,11-dihydro-2-fluoro-5H-dibenzo[a,d]cyclohepten-5-onehydrochloride, respectively.

Step c

Following the procedure of Example 3, step (c) and in the place of10-(2-dimethylaminoethyl)-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5-onehydrochloride, and starting with the correspondingly letteredintermediate of Step (b) of this Example, the following intermediatesare obtained:

(a)10-(2-dimethylaminoethyl)-10,11-dihydro-2,7-difluoro-5-methyl-5H-dibenzo[a,d]cyclohepten-5-ol,

(b)10-(2-dimethylaminoethyl)-10,11-dihydro-7-fluoro-5-methyl-5H-dibenzo[a,d]cyclohepten-5-ol,

(c)10-(2-dimethylaminoethyl)-10,11-dihydro-8-fluoro-5-methyl-5H-dibenzo[a,d]cyclohepten-5-ol,

(d)10-(2-diethylaminoethyl)-10,11-dihydro-5-methyl-5H-dibenzo[a,d]cyclohepten-5-ol,or

(e)10-(2-dimethylaminoethyl)-10,11-dihydro-2-fluoro-5-methyl-5H-dibenzo[a,d]cyclohepten-5-ol,respectively.

Following the procedure of Example 3, Step a) and in place of10-(2-dimethylaminoethyl)-10,11-dihydro-5-methyl-5H-dibenzo[a,d]cyclohepten-5-ol,and starting with the correspondingly lettered lintermediate of Step (c)of the example, the following products are obtained:

(a)10-(2-dimethylaminoethyl)-10,11-dihydro-2,7-difluoro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate,

(b)10-(2-dimethylaminoethyl)-10,11-dihydro-7-fluoro-5-methylene-5H-dibenzodibenzo[a,d]cycloheptene maleate,

(c)10-(2-dimethylaminoethyl)-10,11-dihydro-8-fluoro-5-methylene-5H-dibenzo[a,d]cycloheptene maleate,

(d)10-(2-diethylaminoethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate, or

(e)10-(2-dimethylaminoethyl)-10,11-dihydro-2-fluoro-5-methylene-5H-dibenzo[a,d]cycloheptene maleate, m.p. 140°-142° C., respectively.

The 10-(2-dimethylaminoethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cycloheptene maleate and the10-(2-dimethylaminoethyl)-10,11-dihydro-7-fluoro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate are effective antidepressant agents when orally administered toan animal suffering from depression at a dosage of 100 mg. four timesper day.

EXAMPLE 5 Step a10-(2-dimethylaminoethyl)-10,11-dihydro-5-trimethylsilylmethyl-5H-dibenzo[a,d]cyclohepten-5-ol

A Grignard reagent is prepared by conventional techniques from 12.2 g.(0.1 mole) trimethylsilylmethyl chloride and 24.3 g. magnesium metal(0.1 g. atom) and 200 ml. ether. The resulting solution is treated with27.9 g. (0.1 mole) of10-(2-dimethylaminoethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-onein 100 ml. ether. Stirring is initiated and the mixture is heated atreflux for 5 hours, then cooled in ice and hydrolyzed with 150 ml. ofsaturated ammonium chloride. The layers are separated and the etherdried over anhydrous magnesium sulfate and evaporated to give10-(2-dimethylaminoethyl)-10,11-dihydro-5-trimethylsilylmethyl-5H-dibenzo[a,d]cyclohepten-5-ol.

Following the above procedure and using in place of10-(2-dimethylaminoethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-onean equivalent amount of

(a)10-(2-dimethylaminoethyl)-10,11-dihydro-2,7-difluoro-5H-dibenzo[a,d]cyclohepten-5-one,

(b)10-(2-dimethylaminoethyl)-10,11-dihydro-7-fluoro-5H-dibenzo[a,d]cyclohepten-5-one,

(c)10-(2-dimethylaminoethyl)-10,11-dihydro-8-fluoro-5H-dibenzo[a,d]cyclohepten-5-one,

(d)10-(2-diethylaminoethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one,or

(e)10-(2-dimethylaminoethyl)-10,11-dihydro-2-fluoro-5H-dibenzo[a,d]cyclohepten-5-one,

there is obtained

(a)10-(2-dimethylaminoethyl)-10,11-dihydro-2,7-difluoro-5-trimethylsilylmethyl-5H-dibenzo[a,d]cyclohepten-5-ol,

(b)10-(2-dimethylaminoethyl)-10,11-dihydro-7-fluoro-5-trimethylsilymethyl-5H-dibenzo[a,d]cyclohepten-5-ol,

(c)10-(2-dimethylaminoethyl)-10,11-dihydro-8-fluoro-5-trimethylsilyimethyl-5H-dibenzo[a,d]cyclohepten-5-ol,

(d)10-(2-diethylaminoethyl)-10,11-dihydro-5-trimethylsilylmethyl-5H-dibenzo[a,d]cyclohepten-5-ol,or

(e)10-(2-dimethylaminoethyl)-10,11-dihydro-2-fluoro-5-trimethylsilylmethyl-5H-dibenzo[a,d]cyclohepten-5-ol,respectively.

Step b10-(2-dimethylaminoethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate

A suspension of 24 g. (0.1 mole) of sodium hydride in 200 ml. oftetrahydrofuran is cooled to 0° C and is added to a solution of 36.7 g.(0.1 mole)10-(2-dimethylaminoethyl)-10,11-dihydro-5-trimethylsilyl-methyl-5H-dibenzo[a,d]cyclohepten-5olin 200 ml. of tetrahydrofuran while maintaining temperature at 0° C.After the addition is complete, the mixture is heated to reflux for 5hours. The resultant mixture is cooled to 0° C. and treated with 15 ml.of methanol to remove any unreacted sodium hydride and the solvents areremoved in vacuo. The oily residue is distilled at 140° C./0.5 mm. andthe distillate is dissolved in ethanol and treated with maleic acid. Theprecipitate is filtered and recyrstallized from diethylether-ethanol1:1, to give10-(2-dimethylaminoethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate, m.p. 171 to 172° C.

Following the above procedure and using in place of10-(2-dimethylaminoethyl)-10,11-dihydro-5-trimethylsilylmethyl-5H-dibenzo[a,d]cyclohepten-5-olan equivalent amount of

(a)10-(2-dimethylaminoethyl)-10,11-dihydro-2,7-difluoro-5-trimethylsilylmethyl-5H-dibenzo[a,d]cyclohepten-5-ol,

(b)10-(2-dimethylaminoethyl)-10,11-dihydro-7-fluoro-5-trimethylsilylmethyl-5H-dibenzo[a,d]cyclohepten-5-ol,

(c)10-(2-dimethylaminoethyl)-10,11-dihydro-8-fluoro-5-trimethylsilylmethyl-5H-dibenzo[a,d]cyclohepten-5-ol,

(d)10-(2-diethylaminoethyl)-10,11-dihydro-5-trimethylsilylmethyl-5H-dibenzo[a,d]cyclohepten-5-ol, or

(e)10-(2-dimethylaminoethyl)-10,11-dihydro-2-fluoro-5-trimethylsilylmethyl-5H-dibenzo[a,d]cyclohepten-5-ol,

there is obtained

(a)10-(2-dimethylaminoethyl)-10,11-dihydro-2,7-difluoro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate,

(b)10-(2-dimethylaminoethyl)-10,11-dihydro-7-fluoro-5-methylene-5H-dibenzo[a,d]cycloheptene maleate;

(c)10-(2-dimethylaminoethyl)-10,11-dihydro-8-fluoro-5-methylene-5H-dibenzo[a,d]cycloheptene maleate,

(d)10-(2-diethylaminoethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate, or

(e)10-(2-dimethylaminoethyl)-10,11-dihydro-2-fluoro-5-methylene-5H-dibenzo[a,d]cycloheptene maleate, respectively.

EXAMPLE 6 Step a₁10-(2-dimethylaminoethyl)-10,11-dihydro-5-phenylthiomethyl-5H-dibenzo[a,d]cyclohepten-5-benzoate.

A solution of phenylthiomethyllithium (˜0.5 m) is prepared by reacting6.22 g. (0.05 mole) of thioanisole in 72 ml. of dry tetrahydrofuran with22.0 ml. of 2.3M solution of phenyllithium for 15 hours at roomtemperature under nitrogen. A solution of 1.94 g. (0.007 mole) of10-(2-dimethylaminoethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-onein 40 ml. of tetrahydrofuran is then added to a 42 ml. (˜0.021 mole)portion of the phenylthiomethyllithium with ice-cooling. Stirring isinitiated at room temperature for 24 hours. The resulting10-(2-dimethylaminoethyl)-10,11-dihydro-5-phenylthiomethyl-5H-dibenzo[a,d]cycloheptene-5-olis then poured onto a saturated salt solution and extracted with etherand the ether solution dried over anhydrous magnesium sulfate. The ethersolution is cooled in ice and treated with 4.5 ml. of n-butyllithium inhexane (1.54 M solution 0.007 ice and 0.96 ml. (0.008 mole) of benzoylchloride in 10 ml. ether is then added. The mixture is stirred for 3hours at room temperature, diluted with ether and washed with water,saturated with sodium bicarbonate and then washed again with water. Theether is dried over anhydrous magnesium sulfate, filtered and evaporatedand the residue purified to give10-(2-dimethylaminoethyl)-10,11-dihydro-5-phenylthiomethyl-5H-dibenzo[a,d]cyclohepten-5-benzoate.

Following the above procedure and using in place of10-(2-dimethylaminoethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-onean equivalent amount of

(a)10-(2-dimethylaminoethyl)-10,11-dihydro-2,7-difluoro-5H-dibenzo[a,d]cyclohepten-5-one,

(b)10-(2-dimethylaminoethyl)-10,11-dihydro-7-fluoro-5H-dibenzo[a,d]cyclohepten-5-one,

(c)10-(2-dimethylaminoethyl)-10,11-dihydro-8-fluoro-5H-dibenzo[a,d]cyclohepten-5-one,

(d)10-(2-diethylaminoethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one,or

(e)10-(2-dimethylaminoethyl)-10,11-dihydro-2-fluoro-5H-dibenzo[a,d]cyclohepten-5-one,

there is obtained

(a)10-(2-dimethylaminoethyl)-10,11-dihydro-2,7-difluoro-5-phenylthiomethyl-5H-dibenzo[a,d]cyclohepten-5-benzoate,

(b)10-(2-dimethylaminoethyl)-10,11-dihydro-7-fluoro-5-phenylthiomethyl-5H-dibenzo[a,d]cyclohepten-5-benzoate,

(c)10-(2-dimethylaminoethyl)-10,11-dihydro-8-fluoro-5-phenylthiomethyl-5H-dibenzo[a,d]cyclohepten-5-benzoate,

(d) 10-(2-diethylaminoethyl)-10,11-dihydro-5-phenylthiomethyl-5H-dibenzo[a,d]cyclohepten-5-benzoate, or

(e)10-(2-dimethylaminoethyl)-10,11-dihydro-2-fluoro-5-phenylthiomethyl-5H-dibenzo[a,d]cyclohepten-5-benzoate,

through the corresponding intermediates

(a)10-(2-dimethylaminoethyl)-10,11-dihydro-2,7-difluore-5-phenylthiomethyl-5H-dibenzo[a,d]cyclohepten-5-ol,

(b)10-(2-dimethylaminoethyl)-10,11-dihydro-7-fluoro-5-phenylthiomethyl-5H-dibenzo[a,d]cyclohepten-5-ol,

(c)10-(2-dimethylaminoethyl)-10,11-dihydro-8-fluoro-5-phenylthiomethyl-5H-dibenzo[a,d]cyclohepten-5-ol,

(d)10-(2-(diethylaminoethyl)-10,11-dihydro-5-phenylthiomethyl-5H-dibenzo[a,d]cyclohepten-5-ol, or

(e)10-(2-dimethylaminoethyl)-10,11-dihydro-2-fluoro-5-phenylthiomethyl-5H-dibenzo[a,d]cyclohepten-5-ol,respectively.

Step b10-(2-dimethylaminoethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate.

To a refluxing solution of 0.28 g. of lithium (0.04 mole) in 150 ml.liquid ammonia under nitrogen there is added a solution of 2.29 g. of10-(2-dimethylaminoethyl)-10,11-dihydro-5-phenylthiomethyl-5H-dibenzo[a,d]cyclohepten-5-benzoate(0.004 mole) in 50 ml. ether over about 30 minutes. Reflux is continuedfor an additional 30 minutes and then the mixture is hydrolyzed by theaddition of ammonium chloride in small portions. The ammonia isevaporated while ether is added in small portions. The resulting mixtureis added to water, the layers separated and the ether washed with 1Nsodium hydroxide and water, dried over anhydrous magnesium sulfate,filtered and evaporated. The residue is dissolved in ethanol and treatedwith maleic acid. The resulting precipitate is filtered andrecrystallized from diethylether-ethanol 1:1 to give10-(2-dimethylaminoethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate, m.p. 171° to 172° C.

Following the above procedure and using in place of10-(2-dimethyl)-aminoethyl)-10,11-dihydro-5-phenylthiomethyl-5H-dibenzo[a,d]cyclohepten-5-benzoatean equivalent amount of

(a)10-(2-dimethylaminoethyl)-10,11-dihydro-2,7-difluoro-5-phenylthiomethyl-5H-dibenzo[a,d]cyclohepten-5-benzoate,

(b)10-(2-dimethylaminoethyl)-10,11-dihydro-7-fluoro-5-phenylthiomethyl-5H-dibenzo[a,d]cyclohepten-5-benzoate,

(c)10-(2-dimethylaminoethyl)-10,11-dihydro-8-fluoro-5-phenylthiomethyl-5H-dibenzo[a,d]cyclohepten-5-benzoate,

(d)10-(2-diethylaminoethyl)-10,11-dihydro-5-phenylthiomethyl-5H-dibenzo[a,d]cyclohepten-5-benzoate,or

(e)10-(2-dimethylaminoethyl)-10,11-dihydro-2-fluoro-5-phenylthiomethyl-5H-dibenzo[a,d]cyclohepten-5-benzoate,

there is obtained

(a)10-(2-dimethylaminoethyl)-10,11-dihydro-2,7-difluoro-5-methylene-5H-dibenzo[a,d]cycloheptenmaleate,

(b)10-(2-dimethylaminoethyl)-10,11-dihydro-7-fluoro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate,

(c)10-(2-dimethylaminoethyl)-10,11-dihydro-8-fluoro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate,

(d)10-(2-diethylaminoethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate, or

(e)10-(2-dimethylaminoethyl)-10,11-dihydro-2-fluoro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate, respectively.

EXAMPLE 7 Step a10-(2-dimethylaminoethyl)-10,11-dihydrospiro[dibenzo[a,d]cyclohepten-5,2'-oxirane]

A mixture of 27.6 g. of sodium hydride (0.12 mole) and 26.4 g.trimethyloxosulfonium iodide is treated slowly with 200 ml.dimethylsulfoxide. Stirring is initiated and a vigorous evolution of H₂ensued, which stopped after the addition is complete. The resultingmixture is then treated with 27.9 g. (0.1 mole) of10-(2-dimethylaminoethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-onein 50 ml. dimethylsulfoxide. The reaction mixture is stirred for 15minutes at room temperature and then at 50° C. for 1 hour. The reactionmixture is then cooled and treated with a three fold excess of ice waterand extracted with ether. The ether is washed with water, dried overanhydrous magnesium sulfate, filtered and evaporated. The residue ispurified to give10-(2-dimethylaminoethyl)-10,11-dihydrospiro[dibenzo]cyclohepten-5,2'-oxirane].

Following the above procedure and using in place of10-(2-dimethylaminoethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-onean equivalent amount of

(a)10-(2-dimethylaminoethyl)-10,11-dihydro-2,7-difluoro-5H-dibenzo[a,d]cyclohepten-5-onehydrochloride,

(b)10-(2-dimethylaminoethyl)-10,11-dihydro-7-fluoro-5H-dibenzo[a,d]cyclohepten-5-onehydrochloride,

(c)10-(2-dimethylaminoethyl)-10,11-dihydro-8-fluoro-5H-dibenzo[a,d]cyclohepten-5-onehydrochloride,

(d) 10-(2-diethylaminoethyl)-10,11-dihydro-dibenzo[a,d]cyclohepten-5-onehydrochloride, or

(e)10-(2-dimethylaminoethyl)-10,11-dihydro-2-fluoro-5H-dibenzo[a,d]cyclohepten-5-onehydrochloride,

there is obtained

(a)10-(2-dimethylaminoethyl)-2,7-difluoro-10,11-dihydrospiro[dibenzo[a,d]cyclohepten-5,2'-oxirane],

(b)10-(2-dimethylaminoethyl)-7-fluoro-10,11-dihydrospiro[dibenzo[a,d]cyclohepten-5,2'-oxirane],

(c)10-(2-dimethylaminoethyl)-8-fluoro-10,11-dihydrospiro[dibenzo[a,d]cyclohepten-5,2'-oxirane]

(d)10-(2-diethylaminoethyl)-10,11-dihydrospiro[dibenzo[a,d]cyclohepten-5,2'-oxirane],or

(e)10-(2-dimethylaminoethyl)-2-fluoro-10,11-dihydrospiro[dibenzo[a,d]cyclohepten-5,2'-oxirane],respectively.

Step b10-(2-dimethylaminoethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate.

A mixture of 29.3 g. of10-(2-dimethylaminoethyl)-10,11-dihydrospiro[dibenzo[a,d]cyclohepten-5,2'-oxirane](0.1mole) and 26.2 g. of triphenylphosphine is heated at 180° C. for 5hours. The mixture is cooled and treated with water and ether. Thelayers are separated and the ether washed with water, dried overanhydrous magnesium sulfate, filtered and evaporated. The residue isdistilled at 140° C./0.5 mm. and the distillate is dissolved in ethanoland treated with maleic acid. The precipitate is filtered andrecrystallized from diethylether-ethanol 1:1 to give10-(2-dimethylaminoethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate, m.p. 171°-172° C.

Following the above procedure and using in place of10-(2-dimethylaminoethyl)-10,11-dihydrospiro[dibenzo[a,d]cyclohepten-5,2'-oxirane]an equivalent amount of

(a)10-(2-dimethylaminoethyl)-2,7-difluoro-10,11-dihydrospiro[dibenzo[a,d]cyclohepten-5,2'-oxirane]

(b)10-(2-dimethylaminoethyl)-7-fluoro-10,11-dihydrospiro[dibenzo[a,d]cyclohepten-5,2'-oxirane],

(c)10-(2-dimethylaminoethyl)-8-fluoro-10,11-dihydrospiro[dibenzo[a,d]cyclohepten-5,2'-oxirane],

(d)10-(2-diethylaminoethyl)-10,11-dihydrospiro[dibenzo[a,d]cyclohepten-4,2'-oxirane],or

(e)10-(2-dimethylaminoethyl)-2-fluoro-10,11-dihydrospiro[dibenzo[a,d]cyclohepten-5,2'-oxirane],

there is obtained

(a)10-(2-dimethylaminoethyl)-10,11-dihydro-2,7-difluoro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate,

(b)10-(2-dimethylaminoethyl)-10,11-dihydro-7-fluoro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate,

(c)10-(2-dimethylaminoethyl)-10,11-dihydro-8-fluoro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate

(d)10-(2-diethylaminoethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate, or

(e)10-(2-dimethylaminoethyl)-10,11-dihydro-2-fluoro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate, respectively.

EXAMPLE 810-(2-dimethylaminoethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate.

A mixture of 2.3 g. (0.1 mole) of sodium hydride and 50 ml.dimethylsulfoxide are heated at 75°-80° C. until hydrogen evolution hasceased. The mixture is cooled in an ice-bath and 35.7 g. (0.1 mole) ofmethyl triphenyl phosphonium bromide in 100 ml. dimethyl sulfoxide isadded. The resulting solution is stirred at room temperature for 10minutes. Then 27.9 g. (0.1 mole) of10-(2-dimethylaminoethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-onein 25 ml. of dimethyl sulfoxide is added and the mixture is stirred forone hour at room temperature then treated with a three fold excess ofice-water and extracted with ether. The ether extract is washed withwater, dried over anhydrous magnesium sulfate, filtered and evaporated.The residue is distilled at 140° C./0.5 mm. and the distillate isdissolved in ethanol and treated with maleic acid. The precipitate isfiltered and recrystallized from diethylether-ethanol 1:1 to give10-(2-dimethylaminoethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cycloheptene maleate, m.p. 171°-172° C.

Following the above procedure and using in place of10-(2-dimethylaminoethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one,an equivalent amount of

(a)10-(2-dimethylaminoethyl)-10,11-dihydro-2,7-difluoro-5H-dibenzo[a,d]cyclohepten-5-one,

(b)10-(2-dimethylaminoethyl)-10,11-dihydro-7-fluoro-5H-dibenzo[a,d]cyclohepten-5-one,

(c)10-(2-dimethylaminoethyl)-10,11-dihydro-8-fluoro-5H-dibenzo[a,d]cyclohepten-5-one,

(d)10-(2-diethylaminoethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one,or

(e)10-(2-dimethylaminoethyl)-10,11-dihydro-2-fluoro-5H-dibenzo[a,d]-cyclohepten-5-one,

there is obtained

(a)10-(2-dimethylaminoethyl)-10,11-dihydro-2,7-difluoro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate,

(b)10-(2-dimethylaminoethyl)-10,11-dihydro-7-fluoro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate,

(c)10-(2-dimethylaminoethyl)-10,11-dihydro-8-fluoro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate,

(d)10-(2-diethylaminoethyl)-10,11-dihydro-5H-methylene-5H-dibenzo[a,d]cycloheptenemaleate, or

(e)10-(2-dimethylaminoethyl)-10,11-dihydro-2-fluoro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate, respectively.

EXAMPLE 9 2-(β-[2-dimethylaminoethyl]phenethyl)benzoic acid

To a well stirred suspension of 45 g. of zinc dust, 90 ml. ofconcentrated ammonium hydroxide, 45 ml. of water and 2 ml. of cupricsulfate maintained at 80° C. there is added 14.75 g. (0.05 mole) of3-(2-dimethylaminoethyl)-3,4-dihydro-3-phenylisocoumarin in 50 ml.ethanol for about 30 minutes. The resulting mixture is heated at 85° C.for 30 hours while a slow stream of ammonia is passed through. Themixture is filtered while under heat and the solids washed throughlywith 100 ml. of hot ammonium hydroxide. The combined filtrates arecooled and carefully acidified with concentrated hydrochloric acid togive 2-(β-[-2-dimethylaminoethyl]phenethyl)benzoic acid, m.p. 152° to154° C.

Following the above procedure and using in place of3-(2-dimethylaminoethyl)-3,4-dihydro-3-phenylisocoumarin an equivalentamount of

(a) 3-(4-fluorophenyl)-3-(2-dimethylaminoethyl)-3,4-dihydro-6-fluoroisocoumarin,

(b) 3-(4-fluorophenyl)-3-(2-dimethylaminoethyl)-3,4-dihydro isocoumarin,

(c) 3-(3-fluorophenyl)-3-(2-dimethylaminoethyl)-3,4-dihydro isocoumarin,or

(d) 3-(2-diethylaminoethyl)-3,4-dihydro-3-phenyl isocoumarin, or

(e) 3-(2-dimethylaminoethyl)-3,4-dihydro-6-fluoro isocoumarin,

the following intermediates are obtained,

(a) 4-fluoro-2-(β-[2-dimethylaminoethyl]-p-fluorophenethyl)benzoic acidhydrochloride,

(b) 2-(β-[2-dimethylaminoethyl]-p-fluorophenethyl)benzoic acidhydrochloride,

(c) 2-(β-[2-dimethylaminoethyl)-m-fluorophenethyl)benzoic acidhydrochloride,

(d) 2-(β-[2-diethylaminoethyl]phenethyl)benzoic acid hydrochloride, or

(e) 4-fluoro-2-(β-[2-dimethylaminoethyl]phenethyl)benzoic acidhydrochloride, respectively.

EXAMPLE 10 2-(β-[2-dimethylaminoethyl]phenethyl)benzoic acid ethyl ester

A solution of 29.7 g. (0.1 mole) of2-(β-[2-dimethylaminoethyl]phenethyl)benzoic acid in 200 ml. of ethanolis saturated with gaseous hydrochloride, and the resulting mixture isrefluxed for 18 hours. The solvent is removed in vacuo and the residueis partitioned between ether and 2N sodium hydroxide. The ether extractis dried and evaporated in vacuo to give2-(β-[2-dimethylaminoethyl]phenethyl)benzoic acid ethyl ester.

Following the above procedure and using in place of2-(β-[2-dimethylaminoethyl]phenethyl)benzoic acid an equivalent amountof

(a) 4-fluoro-2-(β-[2-dimethylaminoethyl]-p-fluorophenethyl)benzoic acid,

(b) 2-(β-[2-dimethylaminoethyl]-p-fluorophenethyl)benzoic acid

(c) 2-(β-[2-dimethylaminoethyl]-m-fluorophenethyl)benzoic acid,

(d) 2-(β-[2-diethylaminoethyl]phenethyl)benzoic acid, or

(e) 4-fluoro-2-(β-[2-dimethylaminoethyl]phenethyl)benzoic acid,

the following intermediates are obtained,

(a) 4-fluoro-2-(β-[2-dimethylaminoethyl]-p-fluorophenethyl)benzoic acidethyl ester,

(b) 2-(β-[2-dimethylaminoethyl]-p-fluorophenethyl)benzoic acid ethylester,

(c) 2-(β-[2-dimethylaminoethyl]-m-fluorophenethyl)benzoic acid ethylester, or

(d) 2-(β-[2-diethylaminoethyl]phenethyl)benzoic acid ethyl ester, or

(e) 4-fluoro-2-(β-[2-dimethylaminoethyl]phenethyl)benzoic acid ethylester, respectively.

EXAMPLE 1110-(2-dimethylaminoethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cycloheptene

To a mixture of 5 g. of10-(2-dimethylaminoethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate in 150 ml. of methylene chloride there is added 50 ml. of2N-sodium hydroxide, the mixture is shaken, the methylene chloride isdried, filtered and evaporated in vacuo to give10-(2-dimethylaminoethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cycloheptene.

Following the above procedure and using in place of10-(2-dimethylaminoethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate an equivalent amount of

(a)10-(2-dimethylaminoethyl)-10,11-dihydro-2,7-difluoro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate, or

(b)10-(2-dimethylaminoethyl)-10,11-dihydro-7-fluoro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate,

(c)10-(2-dimethylaminoethyl)-10,11-dihydro-8-fluoro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate,

(d)10-(2-diethylaminoethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate, or

(e)10-(2-dimethylaminoethyl)-10,11-dihydro-2-fluoro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate,

there is obtained

(a)10-(2-dimethylaminoethyl)-10,11-dihydro-2,7-difluoro-5-methylene-5H-dibenzo[a,d]cycloheptene,

(b)10-(2-dimethylaminoethyl)-10,11-dihydro-7-fluoro-5-methylene-5H-dibenzo[a,d]cycloheptene,

(c)10-(2-dimethylaminoethyl)-10,11-dihydro-8-fluoro-5-methylene-5H-dibenzo[a,d]cycloheptene,

(d)10-(2-diethylaminoethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cycloheptene,or

(e)10-(2-dimethylaminoethyl)-10,11-dihydro-2-fluoro-5-methylene-5H-dibenzo[a,d]cycloheptene,respectively.

EXAMPLE 1210-(2-methylaminoethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cycloheptene

A mixture of 15.2 g. (0.055 mole) of10-(2-dimethylaminoethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cyclohepteneand 23.6 g. (0.218 mole) of ethylchloroformate in 125 ml. of toluene isrefluxed under a nitrogen atmosphere for 18 hours. The excess solventand reagent is removed by evaporation in vacuo. The resulting oilproduct is dissolved in a solution of 175 ml. of ethanol, 17 ml of waterand 35 g. (0.625 mole) of potassium hydroxide and refluxed for 10 hours.The solvents are removed in vacuo and the resulting layers are separatedbetween ether and water. The ether is then extracted twice with 2Nhydrochloric acid and the resulting aqueous acid is then made basic andextracted with ether. The excess solvent is then dried and evaporatedand the resulting oil is dissolved in isopropyl alcohol and treated withhydrochloric gas. The residue is then filtered and recrystallized fromisopropyl alcohol to give10-(2-methylaminoethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cycloheptenehydrochloride, m.p. 176°-177° C.

Following the above procedure and using in place of10-(2-dimethylaminoethyl)-10,11-dihydro-5-methylene-5H-dibenzo[a,d]cycloheptene,an equivalent amount of

(a)10-(2-dimethylaminoethyl)-10,11-dihydro-2,7-difluoro-5H-dibenzo[a,d]cycloheptene

(b)10-(2-dimethylaminoethyl)-10,11-dihydro-7-fluoro-5H-dibenzo[a,d]cycloheptene

(c)10-(2-dimethylaminoethyl)-10,11-dihydro-8-fluoro-5H-dibenzo[a,d]cycloheptene

(d)10-(2-dimethylaminoethyl)-10,11-dihydro-2-fluoro-5H-dibenzo[a,d]cycloheptene,or

there is obtained the hydrochloride salt of

(a)10-(2-methylaminoethyl)-10,11-dihydro-2,7-difluoro-5H-dibenzo[a,d]cycloheptene

(b)10-(2-methylaminoethyl)-10,11-dihydro-7-fluoro-5H-dibenzo[a,d]cycloheptene.

(c)10-(2-methylaminoethyl)-10,11-dihydro-8-fluoro-5H-dibenzo[a,d]cycloheptene,or

(d)10-(2-methylaminoethyl)-10,11-dihydro-2-fluoro-5H-dibenzo[a,d]cycloheptene,respectively.

EXAMPLES 13 and 14 Tablets and Capsules Suitable for Oral Administration

Tablets and capsules containing the ingredients indicated below may beprepared by conventional techniques and are useful as anti-depressantsat a dose of one tablet or capsule 2 to 4 times a day.

    ______________________________________                                                               Weight (mg)                                            Ingredients              Tablet  capsule                                      ______________________________________                                        10-(2-dimethylaminoethyl)-10,11-dihydro-5-                                    methylene-5H-dibenzo[a,d]cycloheptene maleate                                                          25       25                                          tragacanth               10      --                                           lactose                  222.5   275                                          corn starch              25                                                   talcum                   15                                                   magnesium stearate       2.5                                                  ______________________________________                                    

EXAMPLES 15 and 16 Sterile Suspension for Injection and Oral LiquidSuspension

The following pharmaceutical compositions are formulated with theindicated amount of active agent using conventional techniques. Theinjectable suspension and the oral liquid suspension representformulations useful as unit doses and may be administered asanti-depressants. The injectable suspension is suitable foradministration once a day where as the oral liquid suspension issuitably administered 2 to 4 times per day for this purpose.

    ______________________________________                                                          Weight (mg)                                                                     Sterile   Oral                                                                Injectable                                                                              Liquid                                          Ingredients         Suspension                                                                              Suspension                                      ______________________________________                                        10-(2-dimethylaminoethyl)-10,11-                                              dihydro-5-methylene-5H-dibenzo                                                [a,d]cycloheptene maleate                                                                         25        25                                              sodium carboxy methyl cellulose                                                                   1.25      12.5                                            U.S.P.                                                                        methyl cellulose    0.4       --                                              polyvinylpyrrolidone                                                                              5         --                                              Lecithin            3         --                                              benzyl alcohol      0.01      --                                              magnesium aluminum silicate                                                                       --        47.5                                            flavor              --        q.s.                                            color               --        q.s.                                            methyl paraben, U.S.P.                                                                            --        4.5                                             propyl paraben, U.S.P.                                                                            --        1.0                                             polysorbate 80 (e.g., Tween 80),                                                                  --        5                                               U.S.P.                                                                        sorbitol solution, 70%, U.S.P.                                                                    --        2,500                                           buffer agent to adjust pH for                                                 desired stability   q.s.      q.s.                                            water               for       q.s. to                                                             injection,                                                                              5 ml.                                                               q.s. to                                                                       1 ml.                                                     ______________________________________                                    

What is claimed is:
 1. A compound of the formula ##STR22## wherein R₁and R₂ each independently represent hydrogen or fluoro, andR₃ ' and R₄ 'are independently lower alkyl having 1 to 2 carbon atoms, or one of R₃ 'and R₄ ' is hydrogen and the other is methyl, provided that at least oneof R₁ and R₂ is fluoro.
 2. A compound of the formula ##STR23## where R₃and R₄ independently represent lower alkyl having 1 to 2 carbon atoms,andR₁, r₂ and the proviso are as defined in claim
 1. 3. A compound ofthe formula ##STR24## where R₁, R₂ and the proviso are as defined inclaim
 1. 4. A compound of the formula ##STR25## where R₁, R₃ and R₄ areas defined in claim 2, or a pharmaceutically acceptable acid additionsalt thereof.
 5. A compound of the formula ##STR26## where R₁, R₃ and R₄are as defined in claim 2, or a pharmaceutically acceptable acidaddition salt thereof.
 6. A compound of the formula ##STR27## where R₁is as defined in claim
 1. 7. A pharmaceutically acceptable acid additionsalt of a compound of claim
 1. 8. The compound of claim 4 which is10-(2-dimethylaminoethyl)-10,11-dihydro-7-fluoro-5-methylene-5H-dibenzo[a,d]cycloheptene.9. The compound of claim 4 which is10-(2-dimethylaminoethyl)-10,11-dihydro-7-fluoro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate.
 10. The compound of claim 1 which is10-(2-dimethylaminoethyl)-10,11-dihydro-2-fluoro-5-methylene-5H-dibenzo[a,d]cycloheptene.11. The compound of claim 1 which is10-(2-dimethylaminoethyl)-10,11-dihydro-2-fluoro-5-methylene-5H-dibenzo[a,d]cycloheptenemaleate.
 12. A method for treating depression which comprisesadministering to a mammal suffering from depression an anti-depressanteffective amount of a compound of claim
 1. 13. A pharmaceuticalcomposition useful in the treatment of depression in mammals comprisingas an active ingredient, a compound according to claim 1 and apharmaceutical carrier therefor, said compound being present in saidcomposition in an amount sufficient to provide a daily dosage of fromabout 30 milligrams to about 750 milligrams of said compound.